DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD) (DeFiD)

• ClinicalTrials.gov Identifier: NCT05966064
• Recruitment Status: Recruiting
• First Posted: July 28, 2023
• Last Update Posted: July 28, 2023
• Sponsor: Natasha Appelman-Dijkstra
• Information provided by (Responsible Party): Natasha Appelman-Dijkstra, Leiden University Medical Center

Tracking Information

• First Submitted Date: June 19, 2023
• First Posted Date: July 28, 2023
• Last Update Posted Date: July 28, 2023
• Actual Study Start Date: June 13, 2023
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 20, 2023)

Denosumab effect on maximal pain score [ Time Frame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months ]

Evaluation of maximal pain score changes after treatment, assessed by Brief Pain Inventory (scale 0 to 10; 0-no pain, 10 worst pain)

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: July 20, 2023)

• Denosumab effect on average pain scores [ Time Frame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months ]
  Evaluation of average pain score changes after treatment, assessed by Brief Pain Inventory (scale 0 to 10; 0-no pain,10 worst pain)
• To evaluate the number of patients with 50% reduction of maximal pain (BPI) [ Time Frame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months ]
  Evaluation of the number of patients with 50% reduction of maximal pain score changes after treatment, asseses by Brief Pain Inventory (scale 0 to 10; 0-no pain, 10 worst pain)
• Denosumab effect on quality of life [ Time Frame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months ]
  Evaluation of Denosumab effect on quality of life, assessed with validated questionnaire SF-36 (scale 0-100, higher scores indicate better health status)
• Denosumab effect on average weekly pain score [ Time Frame: every week from baseline, through study completion, an average of 1 year ]
  Evaluation of Denosumab effect on average weekly pain score assessed through a pain diary with VAS score (scale 0 to 10)
• Denosumab effect on Physical activity assessment assessed through Health Assessment Questionnaire - Disability Index [ Time Frame: baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months ]
  Evaluation of Denosumab effect on on Physical activity assessment (Health Assessment Questionnaire - Disability Index: Health state index scores generally range from less than 0 (where 0 is a health state equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with higher scores indicating higher health utility, though health state preferences can differ between countries.
• Denosumab effect on Physical activity assessment assessed through screenshot of pedometer [ Time Frame: baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months ]
  Evaluation of Denosumab effect on on Physical activity assessment ( screenshot of pedometer of activity during the last week on smartphone, unit measure: number of steps during the last week)
• Evaluation of prevalence of possible neuropathic component of the reported pain [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  to evaluate the prevalence of possible neuropathic component of the reported pain through Pain Detect questionnaire (It is scored from 0 to 38, with total scores of less than 12 considered to represent nociceptive pain, 13-18 possible NeP, and >19 representing >90% likelihood of Neuropathic pain)
• To investigate the number of analgesics used for pain [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  number of used analgesics for pain : unit of measure: number
• To investigate the frequency use of analgesics for pain [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  the frequency use of analgesics for pain (daily, multiple times per day, multiple times per week, monthly, when necessary)
• To investigate the dosage of analgesics used for pain [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  dosage of analgesics used for pain (unit of measure: mg)
• Denosumab effect on serum bone markers [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  effect of denosumab on bone serum markers (alkaline phosphatase (measure unit: U/L), P1NP -Procollagen-1-propeptide (measure unit: ng/ml), Beta-crosslaps (measure unit: ug/L)
• Denosumab effect on serum markers [ Time Frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months ]
  effect of Denosumab on serum calcium(mmol/L), fosfate (mmol/L), PTH (pmol/L)
• Denosumab effect on lesion size [ Time Frame: baseline and after 6 months, and in the case of open label treatment after 12 months ]
  Na18F-PET/CT scan- measurement of lesion size
• Denosumab effect on lesion activity [ Time Frame: baseline and after 6 months, and in the case of open label treatment after 12 months ]
  Na18F-PET/CT scan- ,measurement of Na18F uptake
• disease quantification (Skeletal Burden Score (SBS) [ Time Frame: at baseline, 6 months and after 12 months ]
  nuclear imaging ((Skeletal Burden Score (SBS): scale 0 to 75, higher scores meaning increased disease activity
• Denosumab effect on bone density [ Time Frame: baseline and after 12 months ]
  Dual-energy X-ray absorptiometry (DXA) - bone density measurement ( T-score of -1.0 or above = normal bone density T-score between -1.0 and -2.5 = low bone density, or osteopenia; T-score of -2.5 or lower = osteoporosis)
• Denosumab effect on vertebral fractures [ Time Frame: baseline and after 12 months ]
  Dual-energy X-ray absorptiometry (DXA) - assement of presence of Vertebral Fractures through Vertebral Fractures Assessment (VFA) and changes from baseline until 12 months after
• To assess potential side effects in the form of Atypical femoral fractures [ Time Frame: after 12 months ]
  Dual-energy X-ray absorptiometry (DXA) femur extended

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD)
• Official Title: DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD): a Randomized Double-blind Placebo-controlled Trial

Brief Summary

Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disease, consisting of the replacement of normal bone tissue with fibrous tissue. FD lesions may be isolated in one or more bones or may be associated with endocrinopathies in McCune-Albright syndrome. Bone lesions constitute of weak bone tissue, leading to higher risk of fractures, pain and decreased quality of life. There is no cure for FD lesions and current therapies failed to soothe patients' complaints or to display any effect on progression of the lesions on imaging. However, the RANKL-inhibitor Denosumab demonstrated encouraging results in mouse models and in off-label clinical use, leading to clinical, biochemical and radiographical improvements.

Study's aim is to investigate whether 3-monthly Denosumab will improve the clinical, radiological and biochemical manifestations of FD bone lesions.

• Detailed Description: Eligible patients will be randomized to treatment with either subcutaneous Dmab 120mg or placebo at baseline and 3 months in a blinded fashion. At 6 months, after 2 injections, patients with pain score <4 will exit the study to discontinue study medication and proceed in usual care, while patients with pain score ≥4 or lesional growth will be offered Dmab 120 mg at 6 and 9 months in an open-label design.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Fibrous Dysplasia
• McCune Albright Syndrome

Intervention

• Drug: Denosumab 120 Mg/1.7 Ml Inj
  Denosumab randomized at baseline and after 3 months at 6 and 9 months in case of open label
  Other Name: Xgeva
• Drug: Placebo
  placebo randomized at baseline and after 3 months

Study Arms

• Active Comparator: Denosumab
  Denosumab randomized at baseline and 3 months in a double-blinded fashion and in case of open label at 6 and 9 months
  Intervention: Drug: Denosumab 120 Mg/1.7 Ml Inj
• Placebo Comparator: Placebo
  Placebo randomized at baseline and 3 months in a double-blinded fashion.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 20, 2023): 82
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Symptomatic patients with established diagnosis of FD/MAS and closed growth plates(>18 years)
• Pain in the region of an FD localization, not responding to adequate pain treatment and without mechanical component e.g. impending fracture
• Pain score from FD lesion for maximum or average pain on VAS ≥ 4
• Increased lesional activity defined as increased bone turnover markers (ALP, P1NP or CTX) or increased activity on Na[18F]-PET/CT or bone scintigraphy in at least one lesion
• Normal levels of calcium, parathyroid hormone and vitamin D (supplementation is allowed)
• Treated hypophosphatemia (defined as >0.7 at two separate measures)
• good dental health (last check within the last 12 months)

Exclusion Criteria:

• Active pregnancy wish, pregnancy or nursing
• Pain not related to FD
• Uncontrolled endocrine disease
• Untreated vitamin D deficiency, hypocalcemia or hypophosphatemia
• Previous use of bisphosphonates or Dmab < 6 months before inclusion ('6 months wash out')
• Previously reported severe side effects on Dmab
• Inability to fulfil study requirements
• Poor untreated dental health without intention to get treatment
• Treatment with other bone influencing drugs, such as high doses corticosteroids

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Natasha Appelman-Dijkstra, MD, PhD; +31 625301410; n.m.appelman-dijkstra@lumc.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT05966064
• Other Study ID Numbers: 2022-501705-12-00
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Natasha Appelman-Dijkstra, Leiden University Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Natasha Appelman-Dijkstra
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Natasha Appelman-Dijsktra, MD, PhD; Leiden University Medical Center

• PRS Account: Leiden University Medical Center
• Verification Date: July 2023